Prostate cancer (CaP) is the most common cancer in men of African descent worldwide. African Americans (AA) suffer from the highest rates of CaP in the world, with an average annual incidence rate of 229 per 100,000 in the period 2006-2010 (SEER). The International Agency for Research on Cancer (IARC) GLOBOCAN program estimates that CaP is also the leading cancer in terms of incidence and mortality in men from Africa and the Caribbean. AA men experience the highest rate of aggressive CaP and CaP-specific mortality of any ethnic group in the US. IARC also predicts that CaP deaths in sub-Saharan Africa (SSA) will almost double from 55,522 in 2010 to 105,758 by 2030 (i.e., more than twice as many deaths as in the US). While men of African descent around the world suffer disproportionately from CaP compared to men of other races or ethnicities, our understanding of the reasons for these disparities remains incomplete. To date, few exposure, lifestyle, or environmental influences have been identified in CaP etiology. In contrast, CaP is among the most heritable of common cancers, and over 90 susceptibility loci have been identified. However, many of these loci have not been replicated in AA, in part because of limited African descent sample sizes, incomplete capture of African alleles, and a limited understanding of African genomic architecture. To better understand the etiology of CaP in African descent men, we have initiated a large, multicenter consortium known as Men of African Descent and Carcinoma of the Prostate (MADCaP). Using resources of this consortium, we propose to undertake a multicenter study of CaP in SSA addressing the following Aims: Specific Aim 1: Genetic Susceptibility: Discover novel CaP loci and validate known CaP loci in African men to provide new information about the genetic etiology of CaP. Specific Aim 2. Population Genomics: Evaluate how population differentiation and the recent evolutionary history of African and African American populations inform the underlying reasons for the high rates of CaP in African Americans. This proposal will identify African alleles influence CaP risk in African populations, and will provide information about the African genome that will be of value to a wide range of genome discovery studies in CaP and other diseases.